Matrices formed of polymer and hydrophobic compounds for use in drug delivery

ABSTRACT

A lipid or other hydrophobic or amphiphilic compound (collectively referred to herein as “hydrophobic compounds”) is integrated into a polymeric matrix for drug delivery to alter drug release kinetics. In embodiments where the drug is water soluble, the drug is released over longer periods of time as compared to release from the polymeric matrix not incorporating the hydrophobic compound into the polymeric material. In contrast to methods in which a surfactant or lipid is added as an excipient, the hydrophobic compound is actually integrated into the polymeric matrix, thereby modifying the diffusion of water into the microparticle and diffusion of solubilized drug out of the matrix. The integrated hydrophobic compound also prolongs degradation of hydrolytically unstable polymers forming the matrix, further delaying release of encapsulated drug.

1. This claims priority to U.S. Ser. No. 60/083,636 filed Apr. 30, 1998for “Lipid Polymer Compositions For Enhanced Drug Delivery” by HowardBernstein, Donald E. Chickering and Julie Ann Straub.

BACKGROUND OF THE INVENTION

2. The present invention is generally in the area of drug delivery, andis particularly directed to polymer matrices containing drug and havinglipid or another hydrophobic or amphiphilic compound incorporatedtherein to modify the release kinetics. The matrices are preferably usedfor parenteral delivery. The matrices are preferably in the form ofmicroparticles.

3. Controlled or sustained release compositions have been developed overthe last twenty to thirty years in order to increase the amount of drugdelivered by any of a variety of routes, to sustain drug release in acontrolled fashion, thereby avoiding burst release which can causeelevated but transient drug levels, and to provide a means forcustomized release profiles. These formulations have taken many forms,including microparticles such as microspheres and microcapsules formedof drug and encapsulated or mixed with a natural or synthetic polymer,drug particles mixed with excipients such as surfactants to decreaseagglomeration of the particles, and devices such as the silasticcontrolled release depots which release drug as a function of diffusionof water into the device where it dissolves and releases drug back outthe same entry. It is difficult to achieve sustained release when thedelivery means consists solely of drug or drug and excipient since thedrug tends to solubilize relatively quickly. In contrast,non-biodegradable devices such as the silastic devices must be removedafter usage.

4. Microparticles have been formed using a wide range of techniques,including spray drying, hot melt, solvent evaporation, solventextraction, and mechanical means such as milling and rolling. Themicroparticles are typically formed of a biocompatible material havingdesirable release properties as well as being processible by techniquescompatible with the drug to be delivered. Many drugs are labile andcannot be encapsulated using harsh organic solvents or heat. Most ofthese methods result in formation of a structure where drug is releasedby diffusion of drug out of the microparticle and/or degradation of themicroparticle. In some cases it is desirable to further limit or controldiffusion.

5. It is an object of this invention to provide microparticles whichhave incorporated therein means for limiting diffusion of drug out ofthe microparticle.

6. It is a further object of this invention to provide biodegradablemicroparticles which have incorporated therein means for modifying thedegradation kinetics of the microparticles.

7. It is still another object of the present invention to providemicroparticles particularly well suited for parenteral drug delivery.

SUMMARY OF THE INVENTION

8. A lipid or other hydrophobic or amphiphilic compound (collectivelyreferred to herein as “hydrophobic compounds”) is integrated into apolymeric matrix for drug delivery to alter drug release kinetics. Inone embodiment where the drug is water soluble, the drug is releasedover longer periods of time as compared to release from the polymericmatrix not incorporating the hydrophobic compound into the polymericmaterial. In a further embodiment where the drug has low watersolubility, the drug is released over shorter periods of time ascompared to release from matrix not incorporating the hydrophobiccompound into the polymeric material. In contrast to methods in which asurfactant or lipid is added as an excipient, the hydrophobic compoundis actually integrated into the polymeric matrix, thereby modifying thediffusion of water into the microparticle and diffusion of solubilizeddrug out of the matrix. The integrated hydrophobic compound alsoprolongs degradation of hydrolytically unstable polymers forming thematrix, further delaying release of encapsulated drug.

9. The hydrophobic compound must be incorporated into the matrix and thematrix shaped using a technique which results in integration of thehydrophobic compound into the polymeric matrix, rather than at the outersurface of the matrix. In the preferred embodiment, the matrix is formedinto microparticles. The microparticles are manufactured with a diametersuitable for the intended route of administration. For example, with adiameter of between 0.5 and 8 microns for intravascular administration,a diameter of 1-100 microns for subcutaneous or intramuscularadministration, and a diameter of between 0.5 and 5 mm for oraladministration for delivery to the gastrointestinal tract or otherlumens. A preferred size for administration to the pulmonary system isan aerodynamic diameter of between one and three microns, with an actualdiameter of five microns or more. In the preferred embodiment, thepolymers are synthetic biodegradable polymers. Most preferred polymersare biocompatible hydrolytically unstable polymers like polyhydroxyacids such as polylactic acid-co-glycolic acid, polylactide,polyglycolide or polyactide co-glycolide, which may be conjugated topolyethylene glycol or other materials inhibiting uptake by thereticuloendothelial system (RES).

10. The hydrophobic compounds can be hydrophobic compounds such as somelipids, or amphiphilic compounds (which include both a hydrophilic andhydrophobic component or region). The most preferred amphiphiliccompounds are phospholipids, most preferablydipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine(DSPC), diarachidoylphosphatidylcholine (DAPC),dibehenoylphosphatidylcholine (DBPC), ditricosanoylphosphatidylcholine(DTPC), and dilignoceroylphatidylcholine (DLPC), incorporated at a ratioof between 0.01-60 (w/w polymer), most preferably between 0.1-30 (wlipid/w polymer).

11. Surface properties of the matrix can also be modified. For example,adhesion can be enhanced through the selection of bioadhesive polymers,which may be particularly desirable when the matrix is in the form ofmicroparticles administered to a mucosal surface such as in intranasal,pulmonary, vaginal, or oral administration. Targeting can also beachieved by selection of the polymer or incorporation within or couplingto the polymer to ligands which specifically bind to particular tissuetypes or cell surface molecules. Additionally, ligands may be attachedto the microparticles which effect the charge, lipophilicity orhydrophilicity of the particle.

DETAILED DESCRIPTION OF THE INVENTION

12. Methods are provided for the synthesis of polymeric delivery systemsconsisting of polymer matrices that contain an active agent, such as atherapeutic or prophylactic agent (referred to herein generally as“drug”). The matrices are useful in a variety of drug deliveryapplications, and can be administered by injection, aerosol or powder,orally, or topically. A preferred route of administration is via thepulmonary system or by injection. The incorporation of a hydrophobicand/or amphiphilic compound (referred to generally herein as“hydrophobic compound”) into the polymeric matrix modifies the period ofdrug release as compared with the same polymeric matrix without theincorporated hydrophobic compound, by altering the rate of diffusion ofwater into and out of the matrix and/or the rate of degradation of thematrix.

Reagents for Making Matrix Having Hydrophobic Compound IncorporatedTherein

13. As used herein, the term “matrix” refers to a structure includingone or more materials in which a drug is dispersed, entrapped, orencapsulated. The material can be crystalline, semi-crystalline, oramorphous. The matrix can be in the form of pellets, tablets, slabs,rods, disks, hemispheres, or microparticles, or be of an undefinedshape. As used herein, the term microparticle includes microspheres andmicrocapsules, as well as microparticles, unless otherwise specified.Microparticles may or may not be spherical in shape. Microcapsules aredefined as microparticles having an outer polymer shell surrounding acore of another material, in this case, the active agent. Microspheresare generally solid polymeric spheres, which can include a honeycombedstructure formed by pores through the polymer which are filled with theactive agent, as described below.

Polymers

14. The matrix can be formed of non-biodegradable or biodegradablematrices, although biodegradable matrices are preferred, particularlyfor parenteral administration. Non-erodible polymers may be used fororal administration. In general, synthetic polymers are preferred due tomore reproducible synthesis and degradation, although natural polymersmay be used and have equivalent or even better properties, especiallysome of the natural biopolymers which degrade by hydrolysis, such aspolyhydroxybutyrate. The polymer is selected based on the time requiredfor in vivo stability, i.e. that time required for distribution to thesite where delivery is desired, and the time desired for delivery.

15. Representative synthetic polymers are: poly(hydroxy acids) such aspoly(lactic acid), poly(glycolic acid), and poly(lactic acid-co-glycolicacid), poly(lactide), poly(glycolide), poly(lactide-co-glycolide),polyanhydrides, polyorthoesters, polyamides, polycarbonates,polyalkylenes such as polyethylene and polypropylene, polyalkyleneglycols such as poly(ethylene glycol), polyalkylene oxides such aspoly(ethylene oxide), polyalkylene terepthalates such as poly(ethyleneterephthalate), polyvinyl alcohols, polyvinyl ethers, polyvinyl esters,polyvinyl halides such as poly(vinyl chloride), polyvinylpyrrolidone,polysiloxanes, poly(vinyl alcohols), poly(vinyl acetate), polystyrene,polyurethanes and co-polymers thereof, derivativized celluloses such asalkyl cellulose, hydroxyalkyl celluloses, cellulose ethers, celluloseesters, nitro celluloses, methyl cellulose, ethyl cellulose,hydroxypropyl cellulose, hydroxy-propyl methyl cellulose, hydroxybutylmethyl cellulose, cellulose acetate, cellulose propionate, celluloseacetate butyrate, cellulose acetate phthalate, carboxylethyl cellulose,cellulose triacetate, and cellulose sulphate sodium salt (jointlyreferred to herein as “synthetic celluloses”), polymers of acrylic acid,methacrylic acid or copolymers or derivatives thereof including esters,poly(methyl methacrylate), poly(ethyl methacrylate),poly(butylmethacrylate), poly(isobutyl methacrylate),poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(laurylmethacrylate), poly(phenyl methacrylate), poly(methyl acrylate),poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecylacrylate) jointly referred to herein as “polyacrylic acids”),poly(butyric acid), poly(valeric acid), andpoly(lactide-co-caprolactone), copolymers and blends thereof. As usedherein, “derivatives” include polymers having substitutions, additionsof chemical groups, for example, alkyl, alkylene, hydroxylations,oxidations, and other modifications routinely made by those skilled inthe art.

16. Examples of preferred biodegradable polymers include polymers ofhydroxy acids such as lactic acid and glycolic acid, and copolymers withPEG, polyanhydrides, poly(ortho)esters, polyurethanes, poly(butyricacid), poly(valeric acid), poly(lactide-co-caprolactone), blends andcopolymers thereof.

17. Examples of preferred natural polymers include proteins such asalbumin and prolamines, for example, zein, and polysaccharides such asalginate, cellulose and polyhydroxyalkanoates, for example,polyhydroxybutyrate. The in vivo stability of the matrix can be adjustedduring the production by using polymers such as polylactide co glycolidecopolymerized with polyethylene glycol (PEG). PEG if exposed on theexternal surface may elongate the time these materials circulate sinceit is hydrophilic.

18. Examples of preferred non-biodegradable polymers include ethylenevinyl acetate, poly(meth)acrylic acid, polyamides, copolymers andmixtures thereof.

19. Bioadhesive polymers of particular interest for use in targeting ofmucosal surfaces, as in the gastrointestinal tract, includepolyanhydrides, polyacrylic acid, poly(methyl methacrylates), poly(ethylmethacrylates), poly(butyhnethacrylate), poly(isobutyl methacrylate),poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(laurylmethacrylate), poly(phenyl methacrylate), poly(methyl acrylate),poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecylacrylate).

Solvents

20. A solvent for the polymer is selected based on its biocompatibilityas well as the solubility of the polymer and where appropriate,interaction with the agent to be delivered. For example, the ease withwhich the agent is dissolved in the solvent and the lack of detrimentaleffects of the solvent on the agent to be delivered are factors toconsider in selecting the solvent. Aqueous solvents can be used to makematrices formed of water soluble polymers. Organic solvents willtypically be used to dissolve hydrophobic and some hydrophilic polymers.Preferred organic solvents are volatile or have a relatively low boilingpoint or can be removed under vacuum and which are acceptable foradministration to humans in trace amounts, such as methylene chloride.Other solvents, such as ethyl acetate, ethanol, methanol, dimethylformamide (DMF), acetone, acetonitrile, tetrahydrofuran (THF), aceticacid, dimethyle sulfoxide (DMSO) and chloroform, and combinationsthereof, also may be utilized. Preferred solvents are those rated asclass 3 residual solvents by the Food and Drug Administration, aspublished in the Federal Register vol. 62, number 85, pp. 24301-24309(May 1997).

21. In general, the polymer is dissolved in the solvent to form apolymer solution having a concentration of between 0.1 and 60% weight tovolume (w/v), more preferably between 0.25 and 30%. The polymer solutionis then processed as described below to yield a polymer matrix havinghydrophobic components incorporated therein.

Hydrophobic and Amphiphilic Compounds

22. In general, compounds which are hydrophobic or amphiphilic (i.e.,including both a hydrophilic and a hydrophobic component or region) canbe used to modify penetration and/or uptake of water by the matrix,thereby modifying the rate of diffusion of drug out of the matrix, andin the case of hydrolytically unstable materials, alter degradation andthereby release of drug from the matrix.

23. Lipids which may be used include, but are not limited to, thefollowing classes of lipids: fatty acids and derivatives, mono-, di andtriglycerides, phospholipids, sphingolipids, cholesterol and steroidderivatives, terpenes and vitamins. Fatty acids and derivatives thereofmay include, but are not limited to, saturated and unsaturated fattyacids, odd and even number fatty acids, cis and trans isomers, and fattyacid derivatives including alcohols, esters, anhydrides, hydroxy fattyacids and prostaglandins. Saturated and unsaturated fatty acids that maybe used include, but are not limited to, molecules that have between 12carbon atoms and 22 carbon atoms in either linear or branched form.Examples of saturated fatty acids that may be used include, but are notlimited to, lauric, myristic, palmitic, and stearic acids. Examples ofunsaturated fatty acids that may be used include, but are not limitedto, lauric, physeteric, myristoleic, palmitoleic, petroselinic, andoleic acids. Examples of branched fatty acids that may be used include,but are not limited to, isolauric, isomyristic, isopalmitic, andisostearic acids and isoprenoids. Fatty acid derivatives include12-(((7′-diethylaminocoumarin-3 yl)carbonyl)methylamino)-octadecanoicacid; N-[12(((7′diethylaminocoumarin-3-yl) carbonyl)methyl-amino)octadecanoyl]-2-aminopalmitic acid, Nsuccinyl-dioleoylphosphatidylethanol amine and palmitoyl-homocysteine;and/or combinations thereof. Mono, di and triglycerides or derivativesthereof that may be used include, but are not limited to, molecules thathave fatty acids or mixtures of fatty acids between 6 and 24 carbonatoms, digalactosyldiglyceride, 1,2-dioleoyl-sn-glycerol;1,2-cdipalmitoyl-sn-3 succinylglycerol; and1,3-dipalmitoyl-2-succinylglycerol.

24. Phospholipids which may be used include, but are not limited to,phosphatidic acids, phosphatidyl cholines with both saturated andunsaturated lipids, phosphatidyl ethanolamines, phosphatidylglycerols,phosphatidylserines, phosphatidylinositols, lysophosphatidylderivatives, cardiolipin, and β-acyl-y-alkyl phospholipids. Examples ofphospholipids include, but are not limited to, phosphatidylcholines suchas dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine,dipentadecanoylphosphatidylcholine dilauroylphosphatidylcholine,dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine(DSPC), diarachidoylphosphatidylcholine (DAPC),dibehenoylphosphatidylcholine (DBPC), ditricosanoylphosphatidylcholine(DTPC), dilignoceroylphatidylcholine (DLPC); andphosphatidylethanolamines such as dioleoylphosphatidylethanolamine or1-hexadecyl-2-palmitoylglycerophosphoethanolamine. Syntheticphospholipids with asymmetric acyl chains (e.g., with one acyl chain of6 carbons and another acyl chain of 12 carbons) may also be used.

25. Sphingolipids which may be used include ceramides, sphingomyelins,cerebrosides, gangliosides, sulfatides and lysosulfatides. Examples ofSphinglolipids include, but are not limited to, the gangliosides GM1 andGM2.

26. Steroids which may be used include, but are not limited to,cholesterol, cholesterol sulfate, cholesterol hemisuccinate,6-(5-cholesterol 3β-yloxy)hexyl-6-amino-6-deoxy-1-thio-α-D-galactopyranoside,6-(5-cholesten-3β-tloxy)hexyl-6-amino-6-deoxyl-1-thio-α-Dmannopyranoside and cholesteryl)4′-trimethyl 35 ammonio)butanoate.

27. Additional lipid compounds which may be used include tocopherol andderivatives, and oils and derivatized oils such as stearlyamine.

28. A variety of cationic lipids such as DOTMA,N-[1-(2,3-dioleoyloxy)propyl-N,N,N-trimethylammonium chloride; DOTAP,1,2-dioleoyloxy-3-(trimethylammonio) propane; and DOTB,1,2-dioleoyl-3-(4′-trimethyl-ammonio) butanoyl-sn glycerol may be used.

29. The most preferred lipids are phospholipids, preferably DPPC, DAPC,DSPC, DTPC, DBPC, DLPC and most preferably DPPC, DAPC and DBPC.

30. Other preferred hydrophobic compounds include amino acids such astryptophane, tyrosine, isoleucine, leucine, and valine, aromaticcompounds such as an alkyl paraben, for example, methyl paraben, andbenzoic acid.

31. The content of hydrophobic compound ranges from 0.01-60 (whydrophobic compound /w polymer); most preferably between 0.1-30 (whydrophobic compound /w polymer).

Targeting

32. Microparticles can be targeted specifically or non-specificallythrough the selection of the polymer forming the microparticle, the sizeof the microparticle, and/or incorporation or attachment of a ligand tothe microparticles. For example, biologically active molecules, ormolecules affecting the charge, lipophilicity or hydrophilicity of theparticle, may be attached to the surface of the microparticle.Additionally, molecules may be attached to the microparticles whichminimize tissue adhesion, or which facilitate specific targeting of themicroparticles in vivo. Representative targeting molecules includeantibodies, lectins, and other molecules which are specifically bound byreceptors on the surfaces of cells of a particular type.

Inhibition of Uptake by the RES

33. Uptake and removal of the microparticles can be minimized throughthe selection of the polymer and/or incorporation or coupling ofmolecules which minimize adhesion or uptake. For example, tissueadhesion by the microparticle can be minimized by covalently bindingpoly(alkylene glycol) moieties to the surface of the microparticle. Thesurface poly(alkylene glycol) moieties have a high affinity for waterthat reduces protein adsorption onto the surface of the particle. Therecognition and uptake of the microparticle by the reticulo-endothelialsystem (RES) is therefore reduced.

34. In one method, the terminal hydroxyl group of the poly(alkyleneglycol) is covalently attached to biologically active molecules, ormolecules affecting the charge, lipophilicity or hydrophilicity of theparticle, onto the surface of the microparticle. Methods available inthe art can be used to attach any of a wide range of ligands to themicroparticles to enhance the delivery properties, the stability orother properties of the microparticles in vivo.

Active Agents

35. Active agents which can be incorporated into the matrix for deliveryinclude therapeutic or prophylactic agents. These can be proteins orpeptides, sugars, oligosaccharides, nucleic acid molecules, or othersynthetic or natural agents. The agents may be labeled with a detectablelabel such as a fluorescent label or an enzymatic or chromatographicallydetectable agent.

36. Preferred drugs include antibiotics, antivirals, vaccines,vasodilators, vasoconstrictors, immunomodulatory compounds, includingsteroids, antihistamines, and cytokines such as interleukins, colonystimulating factors, tumor necrosis factor and interferon (α,β, γ),oligonucleotides including genes and antisense, nucleases,bronchodilators, hormones including reproductive hormones, calcitonin,insulin, erthropoietin, growth hormones, and other types of drugs suchas Antiban™.

Methods for Manufacture of Matrix

37. In the most preferred embodiment, microparticles are produced byspray drying. Techniques which can be used to make other types ofmatrices, as well as microparticles, include melt extrusion, compressionmolding, fluid bed drying, solvent extraction, hot melt encapsulation,and solvent evaporation, as discussed below. A major criteria is thatthe hydrophobic compound must be dissolved or melted with the polymer ordispersed as a solid or a liquid in a solution of the polymer, prior toforming the matrix. As a result, the hydrophobic (or amphiphilic)compound is mixed throughout the matrix, in a relatively uniform manner,not just on the surface of the finished matrix. The active agent can beincorporated into the matrix as solid particles, as a liquid or liquiddroplets, or by dissolving the agent in the polymer solvent.

38. a. Solvent Evaporation.

39. In this method the polymer and hydrophobic compound are dissolved ina volatile organic solvent such as methylene chloride. A pore formingagent as a solid or as a liquid may be added to the solution. The activeagent can be added as either a solid or in solution to the polymersolution. The mixture is sonicated or homogenized and the resultingdispersion or emulsion is added to an aqueous solution that may containa surface active agent such as TWEEN™ 20, TWEEN™ 80, PEG or poly(vinylalcohol) and homogenized to form an emulsion. The resulting emulsion isstirred until most of the organic solvent evaporates, leavingmicroparticles. Several different polymer concentrations can be used(0.05-0.60 g/ml). Microparticles with different sizes (1-1000 microns)and morphologies can be obtained by this method. This method isparticularly useful for relatively stable polymers like polyesters.

40. Solvent evaporation is described by E. Mathiowitz, et al., J.Scanning Microscopy, 4, 329 (1990); L. R. Beck, et al., Fertil. Steril.,31, 545 (1979); and S. Benita, et al., J. Pharm. Sci., 73, 1721 (1984),the teachings of which are incorporated herein.

41. Particularly hydrolytically unstable polymers, such aspolyanhydrides, may degrade during the fabrication process due to thepresence of water. For these polymers, the following two methods, whichare performed in completely organic solvents, are more useful.

42. b. Hot Melt Microencapsulation.

43. In this method, the polymer and the hydrophobic compound are firstmelted and then mixed with the solid or liquid active agent. A poreforming agent as a solid or in solution may be added to the solution.The mixture is suspended in a non-miscible solvent (like silicon oil),and, while stirring continuously, heated to 5° C. above the meltingpoint of the polymer. Once the emulsion is stabilized, it is cooleduntil the polymer particles solidify. The resulting microparticles arewashed by decantation with a polymer non-solvent such as petroleum etherto give a free-flowing powder. Microparticles with sizes between one to1000 microns can be obtained with this method. The external surfaces ofparticles prepared with this technique are usually smooth and dense.This procedure is used to prepare microparticles made of polyesters andpolyanhydrides. However, this method is limited to polymers withmolecular weights between 1000-50,000.

44. Hot-melt microencapsulation is described by E. Mathiowitz, et al.,Reactive Polymers, 6, 275 (1987), the teachings of which areincorporated herein. Preferred polyanhydrides include polyanhydridesmade of bis-carboxyphenoxypropane and sebacic acid with molar ratio of20:80 (P(CPP-SA) 20:80) (Mw 20,000) and poly(fumaric-co-sebacic) (20:80)(MW 15,000) microparticles.

45. c. Solvent Removal.

46. This technique was primarily designed for polyanhydrides. In thismethod, the solid or liquid active agent is dispersed or dissolved in asolution of the selected polymer and hydrophobic compound in a volatileorganic solvent like methylene chloride. This mixture is suspended bystirring in an organic oil (such as silicon oil) to form an emulsion.Unlike solvent evaporation, this method can be used to makemicroparticles from polymers with high melting points and differentmolecular weights. The external morphology of particles produced withthis technique is highly dependent on the type of polymer used.

47. d. Spray Drying of Microparticles.

48. Microparticles can be produced by spray drying by dissolving abiocompatible polymer and hydrophobic compound in an appropriatesolvent, dispersing a solid or liquid active agent into the polymersolution, and then spray drying the polymer solution, to formmicroparticles. As defined herein, the process of “spray drying” asolution of a polymer and an active agent refers to a process whereinthe solution is atomized to form a fine mist and dried by direct contactwith hot carrier gases. Using spray drying apparatus available in theart, the polymer solution may be delivered through the inlet port of thespray drier, passed through a tube within the drier and then atomizedthrough the outlet port. The temperature may be varied depending on thegas or polymer used. The temperature of the inlet and outlet ports canbe controlled to produce the desired products.

49. The size of the particulates of polymer solution is a function ofthe nozzle used to spray the polymer solution, nozzle pressure, the flowrate, the polymer used, the polymer concentration, the type of solventand the temperature of spraying (both inlet and outlet temperature) andthe molecular weight. Generally, the higher the molecular weight, thelarger the particle size, assuming the concentration is the same.Typical process parameters for spray drying are as follows: polymerconcentration=0.005-0.20 g/ml, inlet temperature=20-1000°C., outlettemperature=10-300° C., polymer flow rate= 5-2000 ml/min., and nozzlediameter=0.2-4 mm ID. Microparticles ranging in diameter between one andten microns can be obtained with a morphology which depends on theselection of polymer, concentration, molecular weight and spray flow.

50. If the active agent is a solid, the agent may be encapsulated assolid particles which are added to the polymer solution prior tospraying, or the agent can be dissolved in an aqueous solution whichthen is emulsified with the polymer solution prior to spraying, or thesolid may be cosolubilized together with the polymer in an appropriatesolvent prior to spraying.

51. e. Hydrogel Microparticles.

52. Microparticles made of gel-type polymers, such as polyphosphazene orpolymethylmethacrylate, are produced by dissolving the polymer in anaqueous solution, suspending if desired a pore forming agent andsuspending a hydrophobic compound in the mixture, homogenizing themixture, and extruding the material through a microdroplet formingdevice, producing microdroplets which fall into a hardening bathconsisting of an oppositely charged ion or polyelectrolyte solution,that is slowly stirred. The advantage of these systems is the ability tofurther modify the surface of the microparticles by coating them withpolycationic polymers, like polylysine after fabrication. Microparticleparticles are controlled by using various size extruders.

Additives to Facilitate Matrix Formation

53. A variety of surfactants may be added to the continuous phase asemulsifiers if one is used during the production of the matrices.Exemplary emulsifiers or surfactants which may be used (0.1-5% byweight) include most physiologically acceptable emulsifiers. Examplesinclude natural and synthetic forms of bile salts or bile acids, bothconjugated with amino acids and unconjugated such as taurodeoxycholate,and cholic acid. In contrast to the methods described herein, thesesurfactant will coat the microparticle and will facilitate dispersionfor administration.

Pore Forming Agents

54. Pore forming agents can be included in an amount of between 0.01%and 90% weight to volume, to increase matrix porosity and pore formationduring the production of the matrices. The pore forming agent can beadded as solid particles to the polymer solution or melted polymer oradded as an aqueous solution which is emulsified with the polymersolution or is co-dissolved in the polymer solution. For example, inspray drying, solvent evaporation, solvent removal, hot meltencapsulation, a pore forming agent such as a volatile salt, forexample, ammonium bicarbonate, ammonium acetate, ammonium chloride orammonium benzoate or other lyophilizable salt, is first dissolved inwater. The solution containing the pore forming agent is then emulsifiedwith the polymer solution to create droplets of the pore forming agentin the polymer. This emulsion is then spray dried or taken through asolvent evaporation/extraction process. After the polymer isprecipitated, the hardened microparticles can be frozen and lyophilizedto remove any pore forming agents not removed during themicroencapsulation process.

Methods for Administration of Drug Delivery Systems

55. The matrix can be administered orally, topically, to a mucosalsurface (i.e., nasal, pulmonary, vaginal, rectal), or by implantation orinjection, depending on the form of the matrix and the agent to bedelivered. Useful pharmaceutically acceptable carriers include salinecontaining glycerol and TWEEN™ 20 and isotonic mannitol containingTWEEN™ 20. The matrix can also be in the form of powders, tablets, incapsules, or in a topical formulation such as an ointment, gel orlotion.

56. Microparticles can be administered as a powder, or formulated intablets or capsules, suspended in a solution or in a gel (ointment,lotion, hydrogel). As noted above, the size of the microparticles isdetermined by the method of administration. In the preferred embodiment,the microparticles are manufactured with a diameter of between 0.5 and 8microns for intravascular administration, a diameter of 1-100 micronsfor subcutaneous or intramuscular administration, and a diameter ofbetween 0.5 and 5 mm for oral administration for delivery to thegastrointestinal tract or other lumens, or application to other mucosalsurfaces (rectal, vaginal, oral, nasal). A preferred size foradministration to the pulmonary system is an aerodynamic diameter ofbetween one and three microns, with an actual diameter of five micronsor more, as described in U.S. Pat. No. 5,855,913, which issued on Jan.5, 1999, to Edwards, et al. Particle size analysis can be performed on aCoulter counter, by light microscopy, scanning electron microscopy, ortransmittance electron microscopy.

57. In the preferred embodiment, microparticles are combined with apharmaceutically acceptable carrier such as phosphate buffered saline orsaline or mannitol, then an effective amount administered to a patientusing an appropriate route, typically by injection into a blood vessel(i.v.), subcutaneously, intramuscularly (IM) or orally. Microparticlescontaining an active agent may be used for delivery to the vascularsystem, as well as delivery to the liver and renal systems, incardiology applications, and in treating tumor masses and tissues. Foradministration to the pulmonary system, the microparticles can becombined with pharmaceutically acceptable bulking agents andadministered as a dry powder. Pharmaceutically acceptable bulking agentsinclude sugars such as mannitol, sucrose, lactose, fructose andtrehalose. The microparticles also can be linked with ligands thatminimize tissue adhesion or that target the microparticles to specificregions of the body in vivo as described above.

58. The methods and compositions described above will be furtherunderstood with reference to the following non-limiting examples.

EXAMPLE 1 Preparation of PLGA:DAPC Drug Delivery Particles

59. 30 grams of PLGA (50:50) (IV 0.4 dL/g Boehringer Ingelheim), 1.8 gof diarachidoylphosphatidylcholine (Avanti, Birmingham, Ala.) and 495 mgof Azure A (Sigma Chemicals, St. Louis, Mo.) were dissolved in 1000 mlof methylene chloride. The solution was pumped at a flowrate of 20mL/min and spray dried using a Bucchi Lab spray dryer. The inlet airtemperature was 40° C. The dried microparticle powder was collected andstored at −20° C. until analysis. Size of the microparticles wasperformed using a Coulter multisizer II. The microparticles have avolume average mean diameter of 5.982 microns.

60. 18 grams of PLGA (50:50) (IV 0.4 dL/g Boehringer Ingelheim) and 1.08g of diarachidoylphosphatidylcholine (Avanti, Birmingham, Ala.) weredissolved in 600 mL of methylene chloride. 38.9 mg of Eosin Y (SigmaChemicals) was dissolved in 38.9 mL of a 0.18 g/ml ammonium bicarbonatesolution. The eosin solution was emulsified with the polymer solutionusing a Silverson homogenizer at 7000 rpm for 8 minutes. The solutionwas pumped at a flowrate of 20 mL/min and spray dried using a Bucchi Labspray dryer. The inlet air temperature was 40° C. The driedmicroparticle powder was collected and stored at −20° C. until analysis.Size analysis of the microparticles was performed using a Coultermultisizer II. The microparticles have a volume average mean diameter of6.119 microns.

61. Modifications and variations of the present invention will beobvious to those skilled in the art from the foregoing detaileddescription and are intended to come within the scope of the followingclaims.

We claim:
 1. A polymeric matrix for delivery of a therapeutic orprophylactic agent, wherein the matrix is formed of a biocompatiblepolymer having incorporated therein an therapeutic or prophylactic agentand an effective amount of a hydrophobic or amphiphilic compound tomodify the diffusion of water into the matrix and the release of thetherapeutic or prophylactic agent from the matrix.
 2. The matrix ofclaim 1 wherein the matrix is in the form of microparticles.
 3. Thematrix of claim 1 wherein the hydrophobic or amphiphilic compound isincorporated into the matrix at a ratio of between 0.01 and 60 by weightof hydrophobic compound to weight of polymer.
 4. The matrix of claim 3wherein the hydrophobic or amphiphilic compound is a lipid incorporatedinto the matrix at a ratio of between 0.01 and 30 (weight lipid/weightmatrix material).
 5. The matrix of claim 4 wherein the lipid is selectedfrom the group consisting of fatty acids and derivatives, mono-, di andtriglycerides, phospholipids, sphingolipids, cholesterol and steroidderivatives, oils, vitamins and terpenes.
 6. The matrix of claim 5wherein the lipid is a phospholipid selected from the group consistingof phosphatidic acids, phosphatidyl cholines with both saturated andunsaturated lipids, phosphatidyl ethanolamines, phosphatidylglycerols,phosphatidylserines, phosphatidylinositols, lysophosphatidylderivatives, cardiolipin, and β-acyl-y-alkyl phospholipids.
 7. Thematrix of claim 6 wherein the phospholipid is selected from the groupconsisting of dioleoylphosphatidylcholine,dimyristoylphosphatidylcholine, dipentadecanoylphosphatidylcholinedilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine,distearoylphosphatidylcholine, diarachidoylphosphatidylcholine,dibehenoylphosphatidylcholine, ditricosanoylphosphatidylcholine,dilignoceroylphatidylcholine; and phosphatidylethanolamines.
 8. Thematrix of claim 1 wherein the agent is a therapeutic agent.
 9. Thematrix of claim 1 wherein the matrix is formed of a bioadhesive polymer.10. The matrix of claim 1 wherein the matrix is formed of a polymerselected from the group consisting of poly(hydroxy acids),polyanhydrides, polyorthoesters, polyamides, polycarbonates,polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkyleneterepthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters,polyvinyl halides, polyvinylpyrrolidone, polysiloxanes, poly(vinylalcohols), poly(vinyl acetate), polystyrene, polyurethanes andco-polymers thereof, synthetic celluloses, polyacrylic acids,poly(butyric acid), poly(valeric acid), andpoly(lactide-co-caprolactone), ethylene vinyl acetate, copolymers andblends thereof.
 11. The matrix of claim 1 wherein the matrix is formedof a protein or polysaccharide.
 12. The matrix of claim 1 wherein thematrix is in a pharmaceutically acceptable carrier for topicalapplication or application to a mucosal surface.
 13. The matrix of claim1 wherein the matrix is in a pharmaceutically acceptable carrier forinjection.
 14. The matrix of claim 1 wherein the matrix is formulatedfor administration rectally or vaginally.
 15. The matrix of claim 2wherein the microparticles are formulated for pulmonary administration.16. A method for making the matrix of claims 1-15, wherein thehydrophobic compound is distributed into the polymer in an amounteffective to modify the rate of release of the therapeutic orprophylactic agent.
 17. The method of claim 16 wherein the matrix isformed by melting the polymer with the hydrophobic or amphiphiliccompound.
 18. The method of claim 16 wherein the matrix is formed bydissolving the polymer with the hydrophobic or amphiphilic compoundtogether.
 19. The method of claim 16 wherein the solvent is removed byevaporation or extraction.
 20. A method for administering a therapeuticor prophylactic agent comprising administering the matrix of any ofclaims 1-15 to a patient.